Malaria, which is caused by Plasmodium falciparum, infects 200 to 300 million people globally and kills 900,000 (mostly children) every year. Severe malaria-related pathogenesis impacts a broad spectrum of systems and multiple organs. Up to 20% of fatal cases are due to cerebral malaria (CM) and other severe forms of malaria such as severe malaria anemia (SMA). Although the cause of fatal CM is not fully understood, accumulating evidence suggests that complications linked to tissue injury in brain, lung (acute lung injury (ALI), acute respiratory distress syndrome (ARDS)) and kidney (acute renal failure) resulting from malaria contributes to the high morbidity and mortality associated with the disease.
Severe malaria is associated with perturbation of inflammatory cytokines, chemokines, anti-inflammatory cytokines, angiopoietic factors and signalling pathways. Recently, it has been shown that increased level of free HEME produced during malaria infection induces inflammation that damages host vascular endothelium which is responsible for induction of fatal cerebral pathogenesis, as well as ALI and ARDS. HEME oxygenase (HO) is the rate-limiting step enzyme in the degradation of HEME groups to biliverdin, carbon monoxide (CO) and iron.
Despite the availability of treatments for malaria, the mortality associated with severe malaria (e.g., CM, SMA and ARDS) remains high. Most adjunct treatments have not improved the number of fatal outcomes, since these treatments focus mainly on the clearance of parasites in acute disease and not deleterious secondary parasites and host factors that may appear early in infection or remain after treatment. Accordingly, there remains a need for therapeutic approaches for preventing or ameliorating tissue damage caused by malarial infections, as well as other inflammatory disorders and pathogenic infections.
Neuregulin-1 (NRG-1) is a family of growth factors known to effectively attenuate pathology and tissue damage associated with neurodegenerative disorders such as acute ischemic stroke (AIS) and neurotoxin exposure. Neuroprotection from NRG-1 involves inhibition of apoptotic and proinflammatory pathways in target cells such as neuroglial cells. Thus, by inhibiting tissue damage NRG-1 lengthens the therapeutic window in murine AIS models. CM pathogenesis shares some fundamental similarities with both TBI and AIS in occlusion of vessels, glial activation, focal inflammation, activation of apoptotic pathways and reversible and irreversible neuronal tissue damage.